The objective is to obtain information which will improve our understanding of mechanisms influencing arteriolar tone under basal conditions distal to a severe coronary arterial stenosis. Previous work indicates in the setting of a severe coronary arterial stenosis that 1) increased interstitial levels of adenosine are not required for maintenance of arteriolar vasodilation distal to the stenosis and 2) even when basal flow is reduced arteriolar tone is generally greater than minimal distal to the stenosis. Accordingly, we have formulated several hypotheses which will be tested experimentally in order to determine those factors which may be contributing to arteriolar vasodilation and vasoconstriction in this setting. Studies will be conducted in closed chest, sedated but conscious domestic swine instrumented with an artificial coronary arterial stenosis which reduces lumenal diameter by 82%. The stenosis is mounted on a 5 FR Millar catheter equipped with fluid lumen, 20 MHz pulsed Doppler flow velocity sensor and micromanometer pressure gauge. The fluid lumen, micromanometer tip, and Doppler crystal are all positioned on the catheter distal to the distal end of the stenosis. Thus, instantaneous pressure and flow can be recorded from and drugs infused into the coronary circulation distal to the stenosis. Ultra-selective catheterization of the anterior interventricular vein permits sampling of coronary venous blood emanating from myocardium distal to the stenosis. Regional myocardial blood flow also is measured by radioactive microspheres. Flow data is combined with measurement of coronary and systemic hemodynamics as well as regional myocardial oxygen and lactate metabolism in order to evaluate the effects of various interventions upon arteriolar tone distal to the stenosis. A computer model of the stenosed porcine coronary circulation also will be employed to evaluate changes in coronary vascular resistance. We will test the following hypotheses concerning paradoxical coronary arteriolar vasoconstriction in this setting: 1) basal alpha adrenergic tone mediates this response, 2) leukotrienes C4 and/or D4 mediate this effect. Hypotheses to be tested concerning maintenance of coronary arteriolar vasodilation under basal conditions in this setting are 1) chronic local increase in hydrogen ion concentration maintains vasodilation and, 2) activation of histamine receptors (H-1 and/or H-2) maintains reduced arteriolar tone. An improved understandin of those factors active in determining basal steady state levels of arteriolar tone and hence myocardial blood flow distal to a severe coronary arterial stenosis will be helpful in developing better diagnostic and therapeutic modalities for patients with known or suspected ischemic heart disease.